New study links a protein to diabetes, obesity and cancer

A gene may play as large a role in the cause of obesity as the foods we eat, according to new research from City of Hope.

City of Hope researchers found that the protein RLIP76, modeled in above graphic, plays a significant role in weight gain, as well as controlling blood sugar, triglyceride and cholesterol levels.

The study, published in the Journal of Biological Chemistry, found that a protein, called RLIP76, produced by a specific gene, plays a significant role in obesity. Mice lacking the protein were resistant to gaining weight on a high-fat diet and had reduced blood sugar, cholesterol and triglyceride levels. In fact, they gained 40 percent less weight than mice that produced the protein after 12 weeks on a high-fat diet.

Sanjay Awasthi, M.D., a professor of Division of Molecular Diabetes Research and of medical oncology at City of Hope, is one of the study’s lead authors. “The American Medical Association recently defined obesity as a disease, but it’s long been viewed as a syndrome with many contributing factors and no single gene we can pin down — until now. This is conclusive evidence that a single protein dramatically affects development of obesity.”

Of course, such observations are based on animal data, which may or may not apply to humans, but they are undeniably provocative.

With about two-thirds of the U.S. population weighing in as overweight or obese, obesity is one of the nation’s most serious health problems and a global epidemic affecting 300 million people worldwide. Pinpointing this gene’s potential role offers new insights into the mechanism behind obesity — and why it’s so tough to fight, said Sharad Singhal, Ph.D., a research professor in the Division of Diabetes, Endocrinology & Metabolism at City of Hope.

In addition to being thinner after the high-fat diet regimen, the mice without the protein had lower levels of cholesterol and insulin in their blood streams.

“This suggests that a high-fat diet alone is not enough to cause high cholesterol, insulin resistance, obesity, metabolic syndrome or type 2 diabetes,” Singhal said. The protein appears to be an essential factor.

The study is the most recent the team has published examining RLIP76 and its role in disease. The protein is found on the surface of cells and acts as a pump to remove toxic agents that might come in contact with the cell.

Previous studies by Singhal and Awasthi found that cancer cells produce excessive amounts of RLIP76, which makes cancerous cells resistant to radiation and chemotherapy. The protein also plays a role in diabetes, and now obesity. Much study of cancer and other disease focuses on mutated genes leading to a loss of function that causes cancer. Awasthi says maybe researchers have been asking the wrong question.

“Instead, maybe we need to look for the genes that are never mutated in cancer, and this is one of them,” he said. “It’s always present in every type of cancer, and it’s increased in multiple diseases, including diabetes and obesity. Cancer, diabetes and obesity are linked to about 80 percent of all adult mortalities." This protein may play a role in all three.

City of Hope researchers are already working on the next step: identifying a drug that will effectively target the protein.